JP5610050B2 - Method for producing α-fluoroacrylic acid ester - Google Patents

Description

  The present invention relates to a method for producing an α-fluoroacrylic acid ester.

α-Fluoroacrylic acid ester is a synthetic intermediate for pharmaceuticals (for example, antibiotics), a synthetic intermediate for optical fiber sheath materials, a synthetic intermediate for coating materials, a synthetic intermediate for semiconductor resist materials, and functionality. It is useful as a polymer monomer.
Conventionally, the production method of α-fluoroacrylic acid ester with good yield is, for example, a method in which α-fluoroacrylic acid ester is obtained by condensation of α-fluorophosphonoacetate and paraformaldehyde, A method (Patent Document 1) is proposed in which the condensation is carried out in an aqueous medium in the presence of a weak inorganic base.

JP-A-5-201921

However, in Patent Document 1, the yield of α-fluoroacrylic acid ester is 82% at the maximum, and a method capable of achieving a higher yield is desired.
In particular, in the case of synthetic intermediates for producing pharmaceuticals, it is desirable that the content of by-products is extremely low from the viewpoint of pharmaceutical safety. For this reason, it is calculated | required that the selectivity of (alpha) -fluoroacrylic acid ester is very high. However, in general, in the method for producing 2-fluoroacrylic acid, the reaction becomes complicated due to the generation of derivatives and the like, the yield of 2-fluoroacrylic acid is low, and the separation thereof is difficult. For this reason, in order to remove by-products and increase the purity of 2-fluoroacrylic acid, a large amount of waste liquid and waste are generated, which is disadvantageous for industrial production.
Accordingly, an object of the present invention is to provide a method for producing an α-fluoroacrylic acid ester having a high raw material conversion rate, a high selectivity, and a high yield.

The inventors have
Formula (1), which is an α-fluoroacrylic ester:
[Where:
R represents an alkyl group which may be substituted with one or more fluorine atoms. ]
The compound represented by
Formula (2):
[Where:
X represents a bromine atom or a chlorine atom. ]
A compound represented by
In the presence of a transition metal catalyst and a base,
Formula (3):
R-OH (3)
(The symbols in the formula are as defined above.)
It has been found that a high raw material conversion rate, high selectivity, and high yield can be obtained by reacting with the alcohol represented by the formula (1) and carbon monoxide, and the present invention has been completed.

  That is, the present invention includes the following aspects.

Item 1.
Formula (1):
[Where:
R represents an alkyl group which may be substituted with one or more fluorine atoms. ]
A process for producing a compound represented by
Formula (2):
[Where:
X represents a bromine atom or a chlorine atom. ]
A compound represented by
In the presence of a transition metal catalyst and a base,
Formula (3):
R-OH (3)
(The symbols in the formula are as defined above.)
The manufacturing method including the process A which obtains the compound represented by said Formula (1) by making it react with the alcohol and carbon monoxide which are represented by these.
Item 2.
Item 2. The production method according to Item 1, wherein the transition metal catalyst is a palladium catalyst.
Item 3.
Item 3. The method according to Item 1 or 2, wherein the base contains an amine and an inorganic base.
Item 4.
Item 4. The method according to any one of Items 1 to 3, wherein Step A is performed at a temperature in the range of 60 to 120 ° C.

  According to the production method of the present invention, α-fluoroacrylic acid ester can be obtained with high raw material conversion, high selectivity, and high yield.

  In the present specification, examples of the “alkyl group” include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, a neopentyl group, and a hexyl group. C1-6 alkyl groups such as

  In the present specification, examples of the “cycloalkyl group” include C 3-8 cycloalkyl groups such as a cyclopentyl group, a cyclohexyl group, and cycloheptyl.

In this specification, the term “(cyclo) alkyl group” is used with the intention of including an alkyl group and a cycloalkyl group.
Formula (1) of the present invention:
[Where:
R represents an alkyl group which may be substituted with one or more fluorine atoms. ]
The production method of the compound represented by
Formula (2):
[Where:
X represents a bromine atom or a chlorine atom. ]
A compound represented by
In the presence of a transition metal catalyst and a base,
Formula (3):
R-OH (3)
(The symbols in the formula are as defined above.)
The process A which reacts with the alcohol and carbon monoxide which are represented by these, and obtains the compound represented by said Formula (1) is included.

  The alkyl group of the “alkyl group optionally substituted with one or more fluorine atoms” represented by R is preferably a methyl group or an ethyl group, and particularly preferably a methyl group.

  The compound represented by the formula (1) is preferably methyl-2-fluoroacrylate or ethyl-2-fluoroacrylate, and particularly preferably methyl-2-fluoroacrylate.

  The compound represented by the formula (2) is a known compound, can be produced by a known method, or is commercially available.

The alcohol represented by the formula (3) is preferably methanol or ethanol, and particularly preferably methanol.
The alcohol represented by the formula (3) can also function as a solvent for the reaction in Step A.
The amount of the alcohol represented by the formula (3) as a reaction raw material in the step A is usually 1 to 100 mol, preferably about 1.2 to 1 mol with respect to 1 mol of the compound represented by the formula (2). 40 moles.
When the alcohol represented by the formula (3) is also used as a solvent for the reaction in the step A, the alcohol is usually used in a large excess with respect to the compound represented by the formula (2). Specifically, when a solvent other than the alcohol is not used, the amount of the alcohol per mole of the compound represented by the formula (2) is usually 0.2 to 10 L, preferably about 0.4 to 5 L. Or 0.5 to 10 L, or about 1 to 5 L.

  Step A is preferably performed in a container such as an autoclave, and carbon monoxide as a reaction raw material in step A can be introduced into the container by a gas containing carbon monoxide such as purified carbon monoxide gas. The carbon monoxide pressure is usually 0.1 to 10 MPaG, preferably 0.5 to 2 MPaG.

Step A is performed in the presence of a transition metal catalyst.
The transition metal catalyst used in step A is, for example, a transition metal catalyst containing one or more transition metals selected from the group consisting of nickel, palladium, platinum, rhodium, ruthenium, iridium and cobalt.
That is, examples of the transition metal catalyst used in Step A include a nickel catalyst, a palladium catalyst, a platinum catalyst, a rhodium catalyst, a ruthenium catalyst, an iridium catalyst, and a cobalt catalyst.
The transition metal is preferably selected from the group consisting of nickel, cobalt and palladium. In one preferred embodiment of the present invention, the transition metal catalyst containing one or more transition metals selected from the group consisting of nickel, cobalt, and palladium is, for example, an organic nickel complex, an organic cobalt complex, or an organic palladium complex. .

  The nickel complex, the cobalt complex, and the palladium complex may mean both those charged as a reagent and those generated in the reaction system.

As a palladium complex, for example,
Zerovalent palladium complex;
A zero-valent palladium complex generated during the reaction from a divalent palladium complex; and a complex obtained by mixing these with at least one compound (ligand) selected from the group consisting of diketone, phosphine, diamine and bipyridyl, etc. Is mentioned.

The zero-valent palladium complex is not particularly limited. For example, Pd ₂ (DBA) ₃ (DBA is dibenzylideneacetone), Pd (COD) ₂ (COD is cycloocta-1,5-diene), Pd (DPPE) (DPPE is 1,2-bisdiphenylphosphinoethane), Pd (PCy ₃ ) ₂ (Cy is a cyclohexyl group), Pd (Pt-Bu ₃ ) ₂ (t-Bu is a t-butyl group) and Pd (PPh ₃ ) ₄ (Ph is a phenyl group) and the like.

Examples of the divalent palladium complex include palladium chloride, palladium bromide, palladium acetate, bis (acetylacetonato) palladium (II), dichloro (η ⁴ -1,5-cyclooctadiene) palladium (II), or these And a complex in which a phosphine ligand such as triphenylphosphine is coordinated. These II-valent palladium complexes are reduced by, for example, reducing species that coexist in the reaction (eg, phosphine, zinc, organometallic reagents, etc.) to form zero-valent palladium complexes.

  The zero-valent palladium complex produced by reduction from the zero-valent palladium complex or the II-valent palladium complex acts with a compound (ligand) such as diketone, phosphine, diamine, or bipyridyl that is added as necessary during the reaction. Thus, it can be converted into a zero-valent palladium complex involved in the reaction. In the reaction, it is not necessarily clear how many of these ligands are coordinated to the zero-valent palladium complex.

These palladium complexes are often used in the reaction by forming a uniform solution with the reaction substrate by using the ligand as described above, but in addition to this, they are dispersed in polymers such as polystyrene and polyethylene. Alternatively, it can be used as a supported heterogeneous catalyst. Such heterogeneous catalysts have process advantages such as catalyst recovery. Specific examples of the catalyst structure include those in which metal atoms are fixed with a polymer phosphine in which phosphine is introduced into a crosslinked polystyrene (PS) chain as shown in the following chemical formula. In addition, the following:
1) Kanbara et al., Macromolecules, 2000, 33, 657 2) Yamamoto et al., J. Polym. Sci., 2002, 40, 2637 3) JP-A-06-32763 4) JP-A 2005 No. 281454 5) The polymer phosphine described in the literature shown in JP2009-527352A can also be used.

(In the formula, PS represents polystyrene and Ph represents a phenyl group.)

  Examples of the diketone include β diketones such as acetylacetone, 1-phenyl-1,3-butanedione, and 1,3-diphenylpropanedione.

  The phosphine includes, for example, one or more substituents selected from the group consisting of an optionally substituted alkyl group, an optionally substituted cycloalkyl group, and an optionally substituted aryl group. It can be a phosphine possessed on an atom. Of these, tri (cyclo) alkylphosphine or triarylphosphine is preferable. Specific examples of the tri (cyclo) alkylphosphine include, for example, tricyclohexylphosphine, triisopropylphosphine, tri-t-butylphosphine, tritexylphosphine, triadamantylphosphine, tricyclopentylphosphine, di-t-butylmethylphosphine, and tribicyclo. And tri (C3-20 (cyclo) alkyl) phosphine such as [2,2,2] octylphosphine and trinorbornylphosphine. Specific examples of the triarylphosphine include tri (monocyclic aryl) phosphine such as triphenylphosphine, trimesitylphosphine, and tri (o-tolyl) phosphine. Among these, triphenylphosphine, tricyclohexylphosphine, and tri-t-butylphosphine are preferable. In addition, 2-dicyclohexylphosphino-2′4′6′-triisopropylbiphenyl, [4- (N, N-dimethylamino) phenyl] di-tert-butylphosphine; and 4,5-bis ( Diphenylphosphino) -9,9-dimethyl-9H-xanthene, 1,4-bis (diphenylphosphino) butane, 1,3-bis (diphenylphosphino) propane, 1,1′-bis (diphenylphosphino) Bidentate ligands such as ferrocene and 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl are also effective.

  Further, as described above, arylphosphine for heterogeneous catalysts in which a phosphine unit is introduced into a polymer chain can also be preferably used. Specific examples include triarylphosphine having one phenyl group of triphenylphosphine bonded to a polymer chain represented by the following chemical formula.

(In the formula, PS represents polystyrene and Ph represents a phenyl group.)

  Examples of the diamine include tetramethylethylenediamine and 1,2-diphenylethylenediamine.

  Of these ligands, phosphine, diamine, and bipyridyl are preferable, triarylphosphine is more preferable, and triphenylphosphine is particularly preferable. Usually, the use of a palladium complex having a bulky ligand such as phosphine can yield the target compound represented by the formula (1) with higher yield.

Examples of the cobalt complex include Co ₂ (CO) ₈ ; and sodium hydride, sodium alkoxide (eg, sodium neopentoxide, sodium tert-amyloxide, sodium tert-butoxide), cobalt acetate, and carbon monoxide. Complex obtained by mixing (eg, CoCRACO)
Etc.

Moreover, as a nickel complex, for example,
Zerovalent nickel complex;
A zero-valent nickel complex generated during the reaction from a II-valent nickel complex; and a complex obtained by mixing these with at least one compound (ligand) selected from the group consisting of diketone, phosphine, diamine and bipyridyl, etc. Is mentioned.

The zero-valent nickel complex is not particularly limited. For example, Ni (COD) ₂ , Ni (CDD) ₂ (CDD is cyclodeca-1,5-diene), Ni (CDT) ₂ (CDT is cyclodeca-1, _{5,9-triene), Ni (VCH) 2 (} VCH is _{4-vinylcyclohexene), Ni (CO) 4,} (PCy 3) 2 Ni-N≡N-Ni (PCy 3) 2, and Ni (PPh ₃ ) ₄ etc. are mentioned.

  Examples of the II-valent nickel complex include nickel chloride, nickel bromide, nickel acetate, bis (acetylacetonato) nickel (II), or a complex in which a phosphine ligand such as triphenylphosphine is coordinated. It is done. These II-valent nickel complexes are reduced, for example, by a reducing species (phosphine, zinc, organometallic reagent, etc.) coexisting during the reaction to produce a zero-valent nickel complex.

  The zero-valent nickel complex produced by reduction from the above-described zero-valent nickel complex or II-valent nickel complex acts as a ligand added as necessary during the reaction to form a zero-valent nickel complex involved in the reaction. It can also be converted. In the reaction, it is not necessarily clear how many of these ligands are coordinated to the zero-valent nickel complex. As the nickel complex, one having a high function of stabilizing the zero-valent nickel complex generated in the system is desirable. Specifically, those having a ligand such as phosphine, diamine and bipyridyl are preferred, and those having phosphine are particularly preferred.

Here, as a phosphine, a trialkyl phosphine or a triaryl phosphine is preferable, for example.
Specific examples of the trialkylphosphine include, for example, tricyclohexylphosphine, triisopropylphosphine, tri-t-butylphosphine, tritexylphosphine, triadamantylphosphine, tricyclopentylphosphine, di-t-butylmethylphosphine, tribicyclo [2, 2,2] octylphosphine, trinorbornylphosphine and the like tri (C3-20 alkyl) phosphine.
Specific examples of the triarylphosphine include tri (monocyclic aryl) phosphine such as triphenylphosphine, trimesitylphosphine, and tri (o-tolyl) phosphine.
Of these, triphenylphosphine, tricyclohexylphosphine, tri-t-butylphosphine and triisopropylphosphine are preferable.

  Further, as described above, arylphosphine for heterogeneous catalysts in which a phosphine unit is introduced into a polymer chain can also be preferably used. Specific examples include triarylphosphine having one phenyl group of triphenylphosphine bonded to a polymer chain represented by the following chemical formula.

(In the formula, PS represents polystyrene and Ph represents a phenyl group.)

  Examples of the diamine include tetramethylethylenediamine and 1,2-diphenylethylenediamine.

  Among these ligands, bulky ligands such as triarylphosphine such as triphenylphosphine and tri (o-tolyl) phosphine; tricyclohexylphosphine; and trit-butylphosphine are preferable. Usually, the target compound represented by the formula (1) can be obtained in a higher yield by using a nickel complex having a bulky ligand such as triarylphosphine.

  The transition metal catalyst is preferably an organic palladium complex from the viewpoint of the yield and selectivity of the compound represented by the formula (1).

The transition metal catalyst may be a supported catalyst in which the transition metal is supported on a support. Such a supported catalyst is advantageous in terms of cost because the catalyst can be reused.
Examples of the carrier include carbon, alumina, silica-alumina, silica, barium carbonate, barium sulfate, calcium carbonate, titanium oxide, zirconium oxide, or zeolite.
The supported catalyst is particularly preferably palladium carbon, for example.

  The amount of the transition metal catalyst is usually 0.002 to 10 mol, preferably 0.005 to 5 mol, and more preferably 0.005 to 1 mol with respect to 1 mol of the compound represented by the formula (2). Mol, still more preferably 0.01 to 1 mol.

Step A is performed in the presence of a base.
Examples of the base used in Step A include amines, inorganic bases, and organometallic bases.
Examples of amines include triethylamine, tri (n-propyl) amine, tri (n-butyl) amine, diisopropylethylamine, cyclohexyldimethylamine, pyridine, lutidine, γ-collidine, N, N-dimethylaniline, and N-methylpiperidine. N-methylpyrrolidine, N-methylmorpholine and the like.
Examples of the inorganic base include lithium hydroxide, potassium hydroxide, sodium hydroxide, calcium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate.
As an organic metal base, for example,
Organic alkali metal compounds such as butyl lithium, t-butyl lithium, phenyl lithium, triphenylmethyl sodium, ethyl sodium;
And organic alkaline earth metal compounds such as methylmagnesium bromide, dimethylmagnesium, phenylmagnesium chloride, phenylcalcium bromide, and bis (dicyclopentadiene) calcium; and alkoxides such as sodium methoxide and t-butylmethoxide.
Preferred examples of the base include lithium hydroxide, triethylamine, potassium carbonate, and lithium carbonate. More preferred examples of the base include triethylamine, potassium carbonate, and lithium carbonate.
A base can be used individually or in combination of 2 or more types.

  The amount of the base is usually 0.2 to 5 mol, preferably about 0.5 to 3 mol, per 1 mol of the compound represented by the formula (2).

The base used in step A is preferably
(a) an amine, and
(b) Contains an inorganic base or an organic metal base.
The base used in step A more preferably contains an amine and an inorganic base, and more preferably consists of an amine and an inorganic base.
In a preferred embodiment of the present invention, the base used in Step A is one or more inorganic bases selected from the group consisting of (a) triethylamine, and (b) lithium hydroxide, potassium carbonate, and lithium carbonate. Containing.
In a more preferred embodiment of the present invention, the base used in Step A is composed of one or more inorganic bases selected from the group consisting of (a) triethylamine, and (b) potassium carbonate and lithium carbonate.

  The amount of the amine is usually 0.2 to 5 mol, preferably about 0.5 to 3 mol, per 1 mol of the compound represented by the formula (2).

  The amount of the inorganic base is usually 1 to 10 mol, preferably about 2 to 5 mol, per 1 mol of the transition metal catalyst.

Step A is usually carried out at a temperature in the range of 10 to 150 ° C, preferably 50 to 120 ° C, more preferably 60 to 110 ° C, still more preferably 60 to 100 ° C, or 60 to 90 ° C.
When the said temperature is too low, there exists a tendency for a raw material conversion rate and a yield to become low.
On the other hand, if the temperature is too high, in the analysis by the analysis method described later, the compound represented by the formula (1) as a raw material and the presence of by-products or decomposition products in the mixture after the reaction in Step A May be guessed.
[Analysis method]
After completion of the reaction, hexafluorobenzene as an internal standard substance is added and stirred, and left to stand for a while to precipitate a salt. The supernatant is diluted with deuterated chloroform and quantified by ¹⁹ F-NMR integration.

In step A, in addition to the alcohol represented by the formula (3) that can also function as a solvent, other solvents may be used. In this case, the amount of alcohol represented by the formula (3) can be reduced.
Examples of the solvent include non-aromatic hydrocarbon solvents such as pentane, hexane, heptane, octane, cyclohexane, decahydronaphthalene, n-decane, isododecane, and tridecane; benzene, toluene, xylene, tetralin, veratrol, diethylbenzene, methyl Aromatic hydrocarbon solvents such as naphthalene, nitrobenzene, o-nitrotoluene, mesitylene, indene, diphenyl sulfide; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, acetophenone, propiophenone, diisobutyl ketone, isophorone; dichloromethane, chloroform, chlorobenzene, etc. Halogenated hydrocarbon solvents of: diethyl ether, tetrahydrofuran, diisopropyl ether, methyl t-butyl ether, dioxane, dimethyl ether Ether solvents such as toxiethane, diglyme, phenetole, 1,1-dimethoxycyclohexane, diisoamyl ether; ethyl acetate, isopropyl acetate, diethyl malonate, 3-methoxy-3-methylbutyl acetate, γ-butyrolactone, ethylene carbonate, propylene carbonate Ester solvents such as dimethyl carbonate and α-acetyl-γ-butyrolactone; nitrile solvents such as acetonitrile and benzonitrile; sulfoxide solvents such as dimethyl sulfoxide and sulfolane; and N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone, N, N-dimethylacrylamide, N, N-dimethylacetoacetamide, N, N-diethylformamide, N, N- Amide solvents such as ethyl acetamide and the like.

  The solvent is preferably an ether solvent such as diethyl ether, tetrahydrofuran, diisopropyl ether, methyl t-butyl ether, dioxane, dimethoxyethane, diglyme, phenetole, 1,1-dimethoxycyclohexane, diisoamyl ether; or N, N -Dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone, N, N-dimethylacrylamide, N, N-dimethylacetoacetamide, N, N-diethylformamide, Amide solvents such as N, N-diethylacetamide.

  In the step A, the solvent is preferably inert to the raw material compound, the catalyst, and the product.

  As the solvent, an organic solvent having a high boiling point (eg, 100 ° C. or higher, more preferably 120 ° C. or higher) is preferably used from the viewpoint of ease of purification of the compound represented by the formula (1). This makes it possible to purify the compound represented by the formula (1) by simple distillation.

  The amount of the solvent used is not particularly limited as long as a part or all of the raw material is dissolved at the reaction temperature. For example, 0.2-10 weight part or 0.5-10 weight part of solvent can be used with respect to 1 weight part of compounds represented by said Formula (2).

What is necessary is just to set the reaction time of the said reaction based on the raw material conversion rate, selectivity, and yield which are desired, for example, specifically 1 to 24 hours normally, Preferably it is 2 to 12 hours.
The reaction time can be shortened by adopting a higher reaction temperature.

According to the production method of the present invention, the conversion rate of the raw material is preferably 90% or more, more preferably 95% or more, and still more preferably 97% or more.
According to the production method of the present invention, the selectivity of the compound represented by the formula (1) is preferably 90% or more, more preferably 95% or more.

  According to the production method of the present invention, the yield of the compound represented by the formula (1) is preferably 85% or more, more preferably 90% or more.

The compound represented by the formula (1) obtained by the production method of the present invention can be purified by a known purification method such as solvent extraction, drying, filtration, distillation, concentration, and a combination thereof, if desired. .
In particular, in the production method of the present invention, the amount of by-products and decomposition products is extremely small, so that the compound represented by the formula (1) having a very high purity can be obtained by a simple method such as distillation.

  EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited to this.

Example 1
In a 50 mL stainless steel autoclave, 0.87 g (6.96 mmol) of 1-bromo-1-fluoroethene, 0.89 g (8.8 mmol) of triethylamine, 0.168 g (0.24 mmol) of dichlorobis (triphenylphosphine) palladium (II) ), 0.060 g (0.80 mmol) of lithium carbonate, and 10 mL of methanol were introduced, 1.0 MPaG of carbon monoxide was introduced, and the mixture was stirred at 90 ° C. for 6 hours.
After completion of the reaction, the autoclave is cooled, and then the unreacted gas is purged and opened, 186 mg (1.0 mmol) of hexafluorobenzene as an internal standard substance is added and stirred, and left for a while to leave the salt. Precipitated. The supernatant was diluted with deuterated chloroform and quantified by ¹⁹ F-NMR integration. As a result, 6.31 mmol (MFA) of 2-fluoroacrylic acid methyl ester (MFA) and unreacted 1-bromo were obtained. The amount of -1-fluoroethene was 0.19 mmol (recovery rate: 3.0%).
The conversion was 97%.
Moreover, four unknown components were recognized by NMR and the selectivity of MFA was 94.5%. The results are shown in the following table.

Example 2
In a 50 mL stainless steel autoclave, 1.02 g (8.18 mmol) of 1-bromo-1-fluoroethene, 0.89 g (8.8 mmol) of triethylamine, 0.168 g of dichlorobis (triphenylphosphine) palladium (II) (0. 24 mmol), 0.060 g (0.80 mmol) of lithium carbonate, and 10 mL of methanol were introduced, and 1.0 MPaG of carbon monoxide was introduced, followed by stirring at 60 ° C. for 7 hours.
After completion of the reaction, the autoclave is cooled, and then the unreacted gas is purged and opened, 186 mg (1.0 mmol) of hexafluorobenzene as an internal standard substance is added and stirred, and left for a while to leave the salt. Precipitated. The supernatant was diluted with deuterated chloroform and quantified by ¹⁹ F-NMR integration. As a result, 3.69 mmol (45% yield) of 2-fluoroacrylic acid methyl ester (MFA) and unreacted 1-bromo-1 were obtained. -The amount of fluoroethene was 4.49 mmol (recovery 55%).
The conversion was 45% and the selectivity was 100%.

Example 3
In a 50 mL stainless steel autoclave, 0.72 g (5.78 mmol) of 1-bromo-1-fluoroethene, 0.89 g (8.8 mmol) of triethylamine, 0.028 g of dichlorobis (triphenylphosphine) palladium (II). 04 mmol), 0.009 g (0.12 mmol) of lithium carbonate, and 10 mL of methanol were introduced, and 1.0 MPaG of carbon monoxide was introduced, followed by stirring at 90 ° C. for 8 hours.
After completion of the reaction, the autoclave is cooled, and then the unreacted gas is purged and opened, 186 mg (1.0 mmol) of hexafluorobenzene as an internal standard substance is added and stirred, and left for a while to leave the salt. Precipitated. The supernatant was diluted with deuterated chloroform and quantified by ¹⁹ F-NMR integration. As a result, 4.6 mmol (80% yield) of 2-fluoroacrylic acid methyl ester (MFA) and unreacted 1-bromo-1- The fluoroethene was 0.94 mmol (recovery rate 16%).
The conversion was 83%. Further, one unknown component was observed by NMR, and the selectivity was 95%.

Example 4
In a 50 mL stainless steel autoclave, 1.06 g (8.48 mmol) of 1-bromo-1-fluoroethene, 0.97 g (9.6 mmol) of triethylamine, 59.1 mg (0.08 mmol) of dichlorobis (tricyclohexylphosphine) palladium (II) ) And 8 mL of methanol, carbon monoxide 1.0 MPaG was introduced, and the mixture was stirred at 100 ° C. for 9 hours.
After completion of the reaction, the autoclave is cooled, and then the unreacted gas is purged and opened, 186 mg (1.0 mmol) of hexafluorobenzene as an internal standard substance is added and stirred, and left for a while to leave the salt. Precipitated. The supernatant was diluted with deuterated chloroform and quantified by ¹⁹ F-NMR integration. As a result, 6.67 mmol (yield 78.6%) of 2-fluoroacrylic acid methyl ester (MFA) and unreacted 1-bromo were obtained. The amount of -1-fluoroethene was 1.59 mmol (recovery rate: 18.8%).
The conversion rate was 80.2%.

Example 5
In a 50 mL stainless steel autoclave, 0.98 g (7.84 mmol) of 1-bromo-1-fluoroethene, 0.97 g (9.6 mmol) of triethylamine, 40.9 mg of bis (tri-t-butylphosphine) palladium (0) (0 0.08 mmol) and 8 mL of methanol were introduced, and 1.0 MPaG of carbon monoxide was introduced, followed by stirring at 100 ° C. for 9 hours.
After completion of the reaction, the autoclave is cooled, and then the unreacted gas is purged and opened, 186 mg (1.0 mmol) of hexafluorobenzene as an internal standard substance is added and stirred, and left for a while to leave the salt. Precipitated. The supernatant was diluted with deuterated chloroform and quantified by ¹⁹ F-NMR integration. As a result, 4.95 mmol of 2-fluoroacrylic acid methyl ester (MFA) (yield 63.1%) and unreacted 1-bromo were obtained. The amount of -1-fluoroethene was 2.60 mmol (recovery rate: 33.1%).
The conversion was 65.3%.

Example 6
In a 50 mL stainless steel autoclave, 1.12 g (8.96 mmol) of 1-bromo-1-fluoroethene, 0.97 g (9.6 mmol) of triethylamine, 14.2 mg (0.08 mmol) of palladium (II) chloride, 2-dicyclohexyl Phosphino-2′4′6′-triisopropylbiphenyl (38.1 mg, 0.08 mmol) and methanol (8 mL) were charged, carbon monoxide (1.0 MPaG) was introduced, and the mixture was stirred at 100 ° C. for 8 hours.
After completion of the reaction, the autoclave is cooled, and then the unreacted gas is purged and opened, 186 mg (1.0 mmol) of hexafluorobenzene as an internal standard substance is added and stirred, and left for a while to leave the salt. Precipitated. The supernatant was diluted with deuterated chloroform and quantified by ¹⁹ F-NMR integration. As a result, 7.64 mmol (yield 85.3%) of 2-fluoroacrylic acid methyl ester (MFA) and unreacted 1-bromo were obtained. The amount of -1-fluoroethene was 1.08 mmol (recovery rate: 12.0%).
The conversion was 87.5%.

Example 7
In a 50 mL stainless steel autoclave, 0.85 g (6.80 mmol) of 1-bromo-1-fluoroethene, 0.97 g (9.6 mmol) of triethylamine, 5.6 mg (0.008 mmol) of dichlorobis (triphenylphosphine) palladium (II) ) And 8 mL of methanol, carbon monoxide 1.0 MPaG was introduced, and the mixture was stirred at 100 ° C. for 7 hours.
After completion of the reaction, the autoclave is cooled, and then the unreacted gas is purged and opened, 186 mg (1.0 mmol) of hexafluorobenzene as an internal standard substance is added and stirred, and left for a while to leave the salt. Precipitated. The supernatant was diluted with deuterated chloroform and quantified by ¹⁹ F-NMR integration. As a result, 4.80 mmol (yield 70.6%) of 2-fluoroacrylic acid methyl ester (MFA) and unreacted 1-bromo were obtained. The amount of -1-fluoroethene was 1.92 mmol (recovery rate 28.2%).
The conversion was 71.4%.

Example 8
In a 50 mL stainless steel autoclave, 0.93 g (7.44 mmol) of 1-bromo-1-fluoroethene, 0.97 g (9.6 mmol) of triethylamine, 56.2 mg (0.08 mmol) of dichlorobis (triphenylphosphine) palladium (II) ) And 8 mL of ethanol, carbon monoxide 1.0 MPaG was introduced, and the mixture was stirred at 100 ° C. for 6 hours.
After completion of the reaction, the autoclave is cooled, and then the unreacted gas is purged and opened, 186 mg (1.0 mmol) of hexafluorobenzene as an internal standard substance is added and stirred, and left for a while to leave the salt. Precipitated. The supernatant was diluted with deuterated chloroform and quantified by ¹⁹ F-NMR integration. As a result, 6.57 mmol (yield 88.3%) of 2-fluoroacrylic acid ethyl ester (MFA) and unreacted 1-bromo were obtained. The amount of -1-fluoroethene was 0.68 mmol (recovery rate: 9.2%).
The conversion was 90.1%.

Example 9
In a 50 mL stainless steel autoclave, 1.04 g (8.32 mmol) of 1-bromo-1-fluoroethene, 0.97 g (9.6 mmol) of triethylamine, 56.2 mg (0.08 mmol) of dichlorobis (triphenylphosphine) palladium (II) ), 0.51 g (16.0 mmol) of methanol, and 8 mL of tetrahydrofuran were introduced, and 1.0 MPaG of carbon monoxide was introduced, followed by stirring at 100 ° C. for 6 hours.
After completion of the reaction, the autoclave is cooled, and then the unreacted gas is purged and opened, 186 mg (1.0 mmol) of hexafluorobenzene as an internal standard substance is added and stirred, and left for a while to leave the salt. Precipitated. The supernatant was diluted with deuterated chloroform and quantified by ¹⁹ F-NMR integrated value. As a result, 7.47 mmol (yield 89.8%) of 2-fluoroacrylic acid methyl ester (MFA) and unreacted 1-bromo were obtained. The amount of -1-fluoroethene was 0.62 mmol (recovery rate 7.4%).
The conversion rate was 91.7%.

Example 10
In a 50 mL stainless steel autoclave, 1.01 g (8.08 mmol) of 1-bromo-1-fluoroethene, 0.97 g (9.6 mmol) of triethylamine, 56.2 mg (0.08 mmol) of dichlorobis (triphenylphosphine) palladium (II) ), 0.51 g (16.0 mmol) of methanol, and 8 mL of N-methylpyrrolidone were introduced, and 1.0 MPaG of carbon monoxide was introduced, followed by stirring at 100 ° C. for 6 hours.
After completion of the reaction, the autoclave is cooled, and then the unreacted gas is purged and opened, 186 mg (1.0 mmol) of hexafluorobenzene as an internal standard substance is added and stirred, and left for a while to leave the salt. Precipitated. The supernatant was diluted with deuterated chloroform and quantified by ¹⁹ F-NMR integration. As a result, 7.30 mmol (90.3% yield) of 2-fluoroacrylic acid methyl ester (MFA) and unreacted 1-bromo were obtained. The amount of -1-fluoroethene was 0.66 mmol (recovery rate 8.2%).
The conversion was 91.5%.

Example 11
In a 50 mL stainless steel autoclave, 0.97 g (7.76 mmol) of 1-bromo-1-fluoroethene, 0.97 g (9.6 mmol) of triethylamine, 85.1 mg (0.08 mmol) of 10% palladium carbon, triphenylphosphine 42 0.08 mg (0.16 mmol) and 8 mL of methanol were charged, and 1.0 MPaG of carbon monoxide was introduced, followed by stirring at 100 ° C. for 6 hours.
After completion of the reaction, the autoclave is cooled, and then the unreacted gas is purged and opened, 186 mg (1.0 mmol) of hexafluorobenzene as an internal standard substance is added and stirred, and left for a while to leave the salt. Precipitated. The supernatant was diluted with deuterated chloroform and quantified by ¹⁹ F-NMR integration. As a result, 5.86 mmol (MFA) of 2-fluoroacrylic acid methyl ester (MFA) and unreacted 1-bromo were obtained. The amount of -1-fluoroethene was 0.71 mmol (recovery rate: 9.2%).
The conversion rate was 87.0%.

Example 12
In a 50 mL stainless steel autoclave, 1.13 g (14.0 mmol) of 1-chloro-1-fluoroethene, 1.38 g (13.7 mmol) of triethylamine, dichlorobis [di-t-butyl (p-dimethylaminophenyl) phosphino] palladium (II) 0.44 g (0.62 mmol) and 6.2 mL of methanol were charged, carbon monoxide 0.7 MPaG was introduced, and the mixture was stirred at 100 ° C. for 13 hours.
After completion of the reaction, the autoclave is cooled, and then the unreacted gas is purged and opened, 186 mg (1.0 mmol) of hexafluorobenzene as an internal standard substance is added and stirred, and left for a while to leave the salt. Precipitated. The supernatant was diluted with deuterated chloroform and quantified by ¹⁹ F-NMR integration. As a result, 2-fluoroacrylic acid methyl ester (MFA) was 5.98 mmol (yield 42.7%) and unreacted 1-chloro. The amount of -1-fluoroethene was 5.07 mmol (recovery rate 36.2%).
The conversion rate was 63.0%.

Example 13
In a 50 mL stainless steel autoclave, 0.92 g (11.4 mmol) of 1-chloro-1-fluoroethene, 1.38 g (13.7 mmol) of triethylamine, 0.40 g of bis (tri-t-butylphosphine) palladium (0) ( 0.62 mmol) and 6.2 mL of methanol were introduced, and 0.7 MPaG of carbon monoxide was introduced, followed by stirring at 100 ° C. for 18 hours.
After completion of the reaction, the autoclave is cooled, and then the unreacted gas is purged and opened, 186 mg (1.0 mmol) of hexafluorobenzene as an internal standard substance is added and stirred, and left for a while to leave the salt. Precipitated. The supernatant was diluted with deuterated chloroform and quantified by ¹⁹ F-NMR integration. As a result, it was found that 2-fluoroacrylic acid methyl ester (MFA) was 8.82 mmol (yield 77.4%) and unreacted 1-chloro. The amount of -1-fluoroethene was 1.89 mmol (recovery: 16.6%).
The conversion was 81.3%.

Example 14
In a 50 mL stainless steel autoclave, 0.99 g (12.3 mmol) of 1-chloro-1-fluoroethene, 1.38 g (13.7 mmol) of triethylamine, 0.46 g (0.62 mmol) of dichlorobis (tricyclohexylphosphine) palladium (II) ) And 6.2 mL of methanol were introduced, and 0.7 MPaG of carbon monoxide was introduced, followed by stirring at 100 ° C. for 10 hours.
After completion of the reaction, the autoclave is cooled, and then the unreacted gas is purged and opened, 186 mg (1.0 mmol) of hexafluorobenzene as an internal standard substance is added and stirred, and left for a while to leave the salt. Precipitated. The supernatant was diluted with deuterated chloroform and quantified by ¹⁹ F-NMR integration. As a result, 2-fluoroacrylic acid methyl ester (MFA) was found to be 2.80 mmol (yield 22.8%) and unreacted 1-chloro. The amount of -1-fluoroethene was 6.82 mmol (recovery: 55.4%).
The conversion rate was 39.0%.

Example 15
In a 50 mL stainless steel autoclave, 1.05 g (13.0 mmol) of 1-chloro-1-fluoroethene, 1.38 g (13.7 mmol) of triethylamine, 0.11 g (0.62 mmol) of palladium chloride, 2-dicyclohexylphosphino- 0.60 g (1.24 mmol) of 2 ′, 4 ′, 6′-triisopropylbiphenyl and 6.2 mL of methanol were charged, 0.7 MPaG of carbon monoxide was introduced, and the mixture was stirred at 100 ° C. for 12 hours.
After completion of the reaction, the autoclave is cooled, and then the unreacted gas is purged and opened, 186 mg (1.0 mmol) of hexafluorobenzene as an internal standard substance is added and stirred, and left for a while to leave the salt. Precipitated. The supernatant was diluted with deuterated chloroform and quantified by ¹⁹ F-NMR integration. As a result, 1.04 mmol (yield 8.0%) of 2-fluoroacrylic acid methyl ester (MFA) and unreacted 1-chloro The amount of -1-fluoroethene was 9.18 mmol (recovery rate 70.6%).
The conversion rate was 20.7%.

Example 16
In a 50 mL stainless steel autoclave, 0.93 g (11.6 mmol) of 1-chloro-1-fluoroethene, 1.38 g (13.7 mmol) of triethylamine, dichloro [4,5-bis (diphenylphosphino) -9,9 ′ -Dimethylxanthene] palladium (II) 47.0 mg (0.06 mmol) and methanol 6.2 mL were charged, carbon monoxide 0.7 MPaG was introduced, and the mixture was stirred at 100 ° C. for 20 hours.
After completion of the reaction, the autoclave is cooled, and then the unreacted gas is purged and opened, 186 mg (1.0 mmol) of hexafluorobenzene as an internal standard substance is added and stirred, and left for a while to leave the salt. Precipitated. The supernatant was diluted with deuterated chloroform and quantified by ¹⁹ F-NMR integration. As a result, 2-fluoroacrylic acid methyl ester (MFA) was found to be 2.19 mmol (yield 18.9%) and unreacted 1-chloro. The amount of -1-fluoroethene was 7.98 mmol (recovery: 68.8%).
The conversion rate was 20.0%.

Example 17
In a 50 mL stainless steel autoclave, 1.03 g (12.8 mmol) of 1-chloro-1-fluoroethene, 1.38 g (13.7 mmol) of triethylamine, 11.0 mg (0.06 mmol) of palladium chloride, 1,3-bis ( Diphenylphosphino) propane 11.0 mg (0.06 mmol) and methanol 6.2 mL were charged, carbon monoxide 0.7 MPaG was introduced, and the mixture was stirred at 100 ° C. for 19 hours.
After completion of the reaction, the autoclave is cooled, and then the unreacted gas is purged and opened, 186 mg (1.0 mmol) of hexafluorobenzene as an internal standard substance is added and stirred, and left for a while to leave the salt. Precipitated. The supernatant was diluted with deuterated chloroform and quantified by ¹⁹ F-NMR integration. As a result, 6.42 mmol (MFA) of 2-fluoroacrylic acid methyl ester (MFA) and unreacted 1-chloro The amount of -1-fluoroethene was 5.15 mmol (recovery rate 40.2%).
The conversion was 57.1%.

Example 18
In a 50 mL stainless steel autoclave, 1.01 g (12.54 mmol) of 1-chloro-1-fluoroethene, 1.38 g (13.7 mmol) of triethylamine, 11.0 mg (0.06 mmol) of palladium chloride, 2,2′-bis (Diphenylphosphino) -1,1′-binaphthyl (38.7 mg, 0.06 mmol) and methanol (6.2 mL) were charged, carbon monoxide (0.7 MPaG) was introduced, and the mixture was stirred at 100 ° C. for 14 hours.
After completion of the reaction, the autoclave is cooled, and then the unreacted gas is purged and opened, 186 mg (1.0 mmol) of hexafluorobenzene as an internal standard substance is added and stirred, and left for a while to leave the salt. Precipitated. The supernatant was diluted with deuterated chloroform and quantified by ¹⁹ F-NMR integration. As a result, 6.16 mmol (yield 49.1%) of 2-fluoroacrylic acid methyl ester (MFA) and unreacted 1-chloro The amount of -1-fluoroethene was 4.89 mmol (recovery: 39.0%).
The conversion rate was 51.8%.

  According to the present invention, an α-fluoroacrylic acid ester useful as a synthetic intermediate can be produced with high raw material conversion, high selectivity, and high yield.

Claims (2)

Formula (1):
[Where:
R represents an alkyl group which may be substituted with one or more fluorine atoms. ]
A process for producing a compound represented by
Formula (2):
[Where:
X represents a bromine atom or a chlorine atom. ]
A compound represented by
In the presence of a palladium catalyst and a base,
Formula (3):
R-OH (3)
(The symbols in the formula are as defined above.)
The process A is obtained by reacting with an alcohol represented by formula (I) and carbon monoxide to obtain a compound represented by the formula (1), and the process A is carried out at a temperature in the range of 60 to 120 ° C. Method. The base is
(a) an amine, and
(b) The method according to claim 1 containing an inorganic base or an organic metal base.